Multiple Severe Obesity Risk Genes in Utah Pedigrees Severe obesity (BMIS35 kg/m2) comprises a special subset of obesity for which the risk of disease, disability, and mortality is extremely high. Severe obesity has a significant genetic component and current hypotheses suggest underlying genes for severe obesity have larger effects (or greater penetrance) than genes contributing to mild or moderate obesity. Improvements in statistical modeling have led to increased published evidence of genetic epistasis and gender-specific effects, supporting the long-held view that obesity is a complex disease involving multiple genes that interact in complex ways. Evidence is presented herein of a new susceptibility gene we have identified for severe obesity, TBC1D1, that clearly segregates in female family members with severe obesity and explains most of the >9 LOD score. The unique set of large Utah pedigrees with many very severely obese subjects led to such dramatic linkage evidence, followed by significant association and biological evidence. Furthermore, evidence is presented that another unlinked locus on chromosome 4q shows strong evidence of statistical interaction with TBC1D1, such that conditioning on TBC1D1 by analyzing only families segregating TBC1D1 increases the 4q LOD score from 1.7 to 5.0. Since the presence of TBC1D1 does not lead to severe obesity in all carriers, the above result suggests that other gene(s) are also necessary for full expression of obesity. We have also published evidence that a locus on chromosome 20 appears to contain two closely linked genes, one with a dominant and one with a recessive effect on severe obesity (LOD=4.9). This locus was placed in a congenic mouse line which also showed evidence for multiple obesity phenotypes. Further, when the chromosome 20 LOD scores from families segregating for TBC1D1 and the 4q locus were examined, there was additional overlap of some pedigrees. This further suggests that these pedigrees contain multiple genes acting together in unknown fashion resulting in the dense aggregation of severe obesity in these pedigrees. This application proposes to identify, through fine mapping and sequencing, the region 4q gene and chromosome 20 gene(s) to examine nonadditive and gender-specific effects of these genes. Because TBC1D1 has already been identified, this study has the advantage of conditioning on a known, common, susceptibility gene in order to find additional genes and model how they might lead to severe obesity. This highly informative set of pedigrees will be used to further unravel the complexity of the genetic underpinnings of severe obesity that may contribute to the understanding of less severe obesity. Validation will be tested in a large case/control series, Polynesian families, and, for chromosome 20, in the congenic mouse model.